Summary The aging-related Alzheimer disease (AD) is one of neurodegenerative disorders (NDDs) and associated with problems with memory, thinking and behavior. Pathologically, AD is characterized with polymerization of amyloid-? (A?) peptides in the brain in a slow and progressive process proceeding the preclinical phase by almost two decades. The other AD trait is intracellular accumulation of hyperphosphorylated tau protein (P-tau) to form soluble and insoluble neurofibrillary tangles. Recent advances in A? imaging and genetics provide a great promise for diagnosing and differentiating the disease form other NDDs. However, no effective treatment has yet been developed because of incomplete conception of the mechanisms underlying pathological development of the disease, especially the role of posttranslational modifications (PTMs), such as glycosylation. Recently, many glycobiology-based technologies have been developed and thus allow predictable discoveries of pivotal roles played by sugar-modified AD-related biomolecules, such as glycosylated amyloid precursor protein (APP), tau protein (T-tau), and secretases. Glycome aberrations have been reported to play many critical roles in the early stages of the disease pathogenesis and progression. However, developing glycan-based tools specifically designed for AD will improve our perception of the disease pathology and might reveal potential biomarkers and disease modifiers, which might pave the way to develop AD-targeted drug delivery for for effective therapy. Herein, we will develop a set of novel glycomic/glycoproteomic tools to investigate the effect of glycan aberrations during the course of AD on the disease pathogenesis and progression by monitoring changes in AD autoantibodies. We believe that our innate immune system is capable to sense small changes during pathological developments and the generated autoantibodies serve as biomarkers at an early stage. The blood-based autoantibodies are noninvasive and independent of brain imaging diagnoses. To increase the sensitivity of AD autoantibodies, the designed tools are specified to AD-associated pathological fragments derived from the most key AD glycoproteins such as APP, tau protein, secretases, TREM2 and APOE. Thus, we expect precise responses and hence more reliable data since the monitored autoantibodies are against AD-associated fragments designed to explore the highest binding affinities. Along with AD-specific tools, we will develop easy one- or two-steps chemoenzymatic labelling strategies to visualize surface glycan epitopes. Taking the advantage of glycotransferases (GTs) as enzymes specific to certain glycan structures and tolerant to substrate modifications, we designed multiple probes that allow detection of surface glycans by multiple approaches. The overall results obtained from this project will be significant for understanding the fundamental mechanism of AD pathology.